Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1

Lassar, Andrew B.; Thayer, Mathew J.; Overell, Robert W.; Weintraub, Harold

doi:10.1016/0092-8674(89)90101-3

Cited by 277 publications

(229 citation statements)

References 34 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…Myogenin is expressed early in embryogenesis in the somite myotome at the time of lineage determination and later during myogenesis in the developing limb (64,77). The myogenin locus is also negatively regulated by growth factor and oncogenic signals and is silenced in the presence of BrdU (7,24,25,43,62,68). It is unknown whether these different regulatory influences are directed at a common control sequence or are mediated by multiple regulatory elements associated with the myogenin gene.…”

Section: Resultsmentioning

confidence: 99%

Analysis of the myogenin promoter reveals an indirect pathway for positive autoregulation mediated by the muscle-specific enhancer factor MEF-2.

Edmondson¹,

Cheng²,

Cserjesi³

et al. 1992

Mol. Cell. Biol.

292

253

View full text Add to dashboard Cite

Transcriptional cascades that specify cell fate have been well described in invertebrates. In mammalian development, however, gene hierarchies involved in determination of cell lineage are not understood. With the recent cloning of the MyoD family of myogenic regulatory factors, a model system has become available with which to study the dynamics of muscle determination in mammalian development. Myogenin, along with other members of the MyoD gene family, possesses the apparent ability to redirect nonmuscle cells into the myogenic lineage. This ability appears to be due to the direct activation of an array of subordinate or downstream genes which are responsible for formation and function of the muscle contractile apparatus. Myogenin-directed transcription has been shown to occur through interaction with a DNA consensus sequence known as an E box (CANNTG) present in the control regions of numerous downstream genes. In addition to activating the transcription of subordinate genes, members of the MyoD family positively regulate their own expression and cross-activate one another's expression. These autoregulatory interactions have been suggested as a mechanism for induction and maintenance of the myogenic phenotype, but the molecular details of the autoregulatory circuits are undefined. Here we show that the myogenin promoter contains a binding site for the myocytespecific enhancer-binding factor, MEF-2, which can function as an intermediary of myogenin autoactivation. Since MEF-2 can be induced by myogenin, these results suggest that myogenin and MEF-2 participate in a transcriptional cascade in which MEF-2, once induced by myogenin, acts to amplify and maintain the myogenic phenotype by acting as a positive regulator of myogenin expression.The formation of skeletal muscle during vertebrate development involves the induction of mesoderm from primary ectoderm and the subsequent generation of proliferating myoblasts that ultimately terminally differentiate in response to environmental cues. The recent discovery of a family of related muscle-specific factors that can convert fibroblasts to myoblasts has contributed to rapid progress toward understanding the molecular events that underlie the establishment of the skeletal muscle phenotype (for reviews, see references 55 and 69). Members of this muscle regulatory gene family include MyoD (21), myogenin (25, 77), myf5 (9), and MRF4/herculin/myf6 (8,48,61), each of which can activate myogenesis when introduced into a wide range of nonmuscle cell types.

show abstract

Section: Resultsmentioning

confidence: 99%

Analysis of the myogenin promoter reveals an indirect pathway for positive autoregulation mediated by the muscle-specific enhancer factor MEF-2.

Edmondson¹,

Cheng²,

Cserjesi³

et al. 1992

Mol. Cell. Biol.

292

253

View full text Add to dashboard Cite

show abstract

“…In one study, 35% of embryonal tumors carried activating mutations of either N-or K-ras (Stratton et al, 1989;Wexler and Helman, 1994). Activated ras has been shown to block myogenic di erentiation by down-regulating myogenic factors such as MyoD and myogenin (Lassar et al, 1989;Konieczny et al, 1989). The chromosomal region at 12q13-15, encoding factors of regulatory signi®cance such as GLI, MDM2 and CDK4 , is frequently ampli®ed in human sarcomas, including some RMS cell lines (Khatib et al, 1993;Berner et al, 1996;Meddeb et al, 1996).…”

Section: Cytogenetic De®nition Of Rhabdomyosarcomamentioning

confidence: 99%

Rhabdomyosarcoma – working out the pathways

1999

View full text Add to dashboard Cite

Rhabdomyosarcomas constitute a collection of childhood malignancies thought to arise as a consequence of regulatory disruption of skeletal muscle progenitor cell growth and di erentiation. Our understanding of the pathogenesis of this neoplasm has recently bene®ted from the study of normal and malignant myogenic cells in vitro, facilitating the identi®cation of diagnostic cytogenetic markers and the elucidation of mechanisms by which myogenesis is regulated. It is now appreciated that the delicate balance between proliferation and di erentiation, mutually exclusive yet intimately associated processes, is normally controlled in large part through the action of a multitude of growth factors, whose signals are interpreted by members of the MyoD family of helix ± loop ± helix proteins, and key regulatory cell cycle factors. The latter have proven to be frequent targets of mutational events that subvert myogenesis and promote the development of rhabdomyosarcoma. Although signi®cant progress has been made in the treatment of rhabdomyosarcoma, patients presenting with metastatic disease or certain high risk features are still faced with a dismal prognosis. Only now are genetically engineered mouse models becoming available that are certain to provide fresh insights into the molecular/genetic pathways by which rhabdomyosarcomas arise and progress, and to suggest novel avenues of therapeutic opportunity.

show abstract

“…Previous studies have shown that approximately one-third carry activating mutations of either K-ras, H-ras or N-ras (Stratton et al, 1989;Wilke et al, 1993;Wexler and Helman, 1994;Yoo and Robinson, 1999;Garcia et al, 2000). Constitutive Ras activation leads to deregulated cell proliferation and blocks myogenic differentiation by downregulating myogenic factors such as MyoD and myogenin (Lassar et al, 1989). Mutations in p53 have also been found in nearly 50% of RMS cases and cell lines (Mulligan et al, 1990;Felix et al, 1992;Merlino and Helman, 1999).…”

Section: Introductionmentioning

confidence: 99%

Cooperation of oncogenic K-ras and p53 deficiency in pleomorphic rhabdomyosarcoma development in adult mice

et al. 2006

View full text Add to dashboard Cite

Human rhabdomyosarcomas (RMSs) frequently demonstrate genetic alterations in ras and p53. To investigate their possible involvement in the tumorigenesis, we generated a knock-in mouse line with oncogenic K-ras, conditionally expressed by Cre/LoxP system on a background of p53 alteration. Electroporation of Cre expression vector in skeletal muscle tissues resulted in the generation of tumor in adults with tumor incidences of 100% at 10 weeks and 40% at 15 weeks, in p53 À/À and p53 À/ þ backgrounds, respectively. The tumor histology was pleomorphic RMS with characteristic bizarre giant cells, positive for desmin and a-sarcomeric actin and exhibiting remarkable increase in total and phosphorylated extracellular signal-regulated protein kinase (ERK)1 and ERK2. Loss of the wild-type p53 was detected in K-rasG12V-expressed tumors of p53 À/ þ mice. Early lesions 3 weeks after electroporation consisted of proliferating populations of myogenic progenitors, including stem cells positive for ScaI antigen, immature cells positive for desmin and neural cell adhesion molecule-positive myotubes. Thus, cooperation of oncogenic K-ras and p53 deficiency resulted in the development of pleomorphic RMS in adult mice, providing a useful mouse model for further detailed studies.

show abstract

Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1

Cited by 277 publications

References 34 publications

Analysis of the myogenin promoter reveals an indirect pathway for positive autoregulation mediated by the muscle-specific enhancer factor MEF-2.

Analysis of the myogenin promoter reveals an indirect pathway for positive autoregulation mediated by the muscle-specific enhancer factor MEF-2.

Rhabdomyosarcoma – working out the pathways

Cooperation of oncogenic K-ras and p53 deficiency in pleomorphic rhabdomyosarcoma development in adult mice

Contact Info

Product

Resources

About